[Magnetic Resonance-guided Focused Ultrasound Ablation:Techniques and Neurological Applications].

Magnetic resonance(MR)-guided focused ultrasound ablation(FUS)is a minimally invasive technique for targeted tissue thermo-ablation and is promising for neuromodulation in various neurological disorders. The effectiveness and safety of this technique have been recognized worldwide. In Japan, the applications of FUS for the treatment of essential tremors and Parkinson's disease have recently been covered under health insurance. The FUS system is composed of a phased-array transducer with 1024 elements, with a beam of ultrasound emerging from each element. The phase and amplitude of the beam are computed and controlled to focus on the target with the calculation of computed tomography(CT)profiles, resulting in optimal thermo-ablation. To utilize FUS safely and effectively, a deep understanding of the physics of this technology is necessary. Furthermore, the technique should be compared with other options including deep brain stimulation(DBS)and radiofrequency thermo-ablation. Although FUS has received attention because of minimally invasive characteristics and a possibility of procedural target refinement, DBS has some advantages on bilateral implantation, a potential of postoperative adjustment, and control of head/leg tremors. In this article, we first reviewed the physics of FUS and demonstrated the typical treatment protocols. Second, we reviewed the outcomes from the existing literature, and revealed the advantages and disadvantages of this procedure, with the evaluation of the optimal condition for FUS.

Gamma knife radiosurgery of craniopharyngioma: results of 30 cases treated at Nagoya Radiosurgery Center.

Evaluation of 30 cases of craniopharyngioma treated by Gamma Knife at Nagoya Radiosurgery Center (NRC), Nagoya Kyoritsu Hospital since July, 2004 has been made. The mean volume of the tumor was 2.64 ml, which was treated with the marginal dose of 11.7 Gy. Mean follow-up period was 79.9 months. The effects were evaluated by MRI findings, neuro-endocrine and hypothalamic signs and symptoms, complications and KPS every 3~6 months. As the results, complete remission was obtained in 8, partial remission in 12, no change in 6, progression in 3, in which two died by hypothalamic invasion. Tumor response rate was 68.9% and control rate 87.9%. Actuarial survival was 96% at 5 and 86% at 10 years. However, progression free survival was 76% and 76%, respectively. Using marginal dose of 11.7Gy to a smaller tumor, better control without complications has been obtained. KPS was excellent in 14, good in 9, fair in 2, poor in 1 and unknown in a case. Finally, there were three deaths, where two were died of tumor progression and one by infirmity. The progression of hypothalamic symptoms other than diabetes insipidus were found in two cases. Volume reduction and effective dose setting will be important for the improvement of QOL and survival after combined microsurgery and radiosurgery of craniopharyngioma.

Dosimetric comparison of absolute and relative dose distributions between tissue maximum ratio and convolution algorithms for acoustic neurinoma plans in Gamma Knife radiosurgery.

BACKGROUND: The treatment planning for Gamma Knife (GK) stereotactic radiosurgery (SRS) that performs dose calculations based on tissue maximum ratio (TMR) algorithm has disadvantages in predicting dose in tissue heterogeneity. The latest version of the planning software is equipped with a convolution dose algorithm as an optional extra and the new algorithm is able to compensate for head inhomogeneity. However, the effect of this improved calculation method requires detailed validation in clinical cases. In this study, we compared absolute and relative dose distributions of treatment plans for acoustic neurinoma between TMR and the convolution calculation. METHODS: Twenty-nine clinically used plans created by TMR algorithm were recalculated by convolution method. Differences between TMR and convolution were evaluated in terms of absolute dose (beam-on time), dosimetric parameters including target coverage, selectivity, conformity index, gradient index, radical homogeneity index and the dose-volume relationship. RESULTS: The discrepancy in estimated absolute dose to the target ranged from 1 to 7 % between TMR and convolution. In addition, dosimetric parameters of the two methods achieved statistical significance. However, it was difficult to see the change of relative dose distribution by visual assessment on a monitor. CONCLUSIONS: Convolution, heterogeneity correction calculation, and the algorithm are necessary to reduce the dosimetric uncertainty of each case in GK SRS.

Assessment of spatial uncertainty in computed tomography-based Gamma Knife stereotactic radiosurgery process with automated positioning system.

BACKGROUND: In this study, we assessed the geometric accuracy of an automated positioning system in Gamma Knife (GK) surgery. Specifically, we looked at the total spatial uncertainty over the entire treatment range of GK stereotactic radiosurgery (SRS) procedures in both the GK model C and the Perfexion (PFX). METHODS: An originally-developed phantom and a radiochromic film were used for obtaining actual dose distributions. The phantom, with inserted films on different axial planes (z = 60, 75, 100, 125, 140 mm), sagittal planes (x = 60, 75, 100, 125, 140 mm), and coronal planes (y = 60, 75, 100, 125, 140 mm), was placed on a Leksell skull frame. Computed tomography (CT) was then performed with a stereotactic localizer box attached to the frame, and dose planning was made using the Leksell GammaPlan treatment planning system. The phantom finally received beam delivery using a single shot of a 4-mm collimator helmet. The discrepancy between the planned shot position and the irradiated center position was evaluated by a dedicated film analysis software. RESULTS: The total uncertainty of CT-based GK SRS was less than 1 mm for almost all measured points over the stereotactic space in both the model C and the PFX. In addition, the geometric accuracy of the automated positioning system was estimated to be less than 0.1 mm and equal to 0.5 mm in the central and peripheral areas, respectively. CONCLUSIONS: We confirmed that the total spatial uncertainties of both the GK model C and the PFX are acceptable for clinical use.

Useful base plate to support the head during Leksell skull frame placement in gamma knife perfexion radiosurgery.

We developed an original base plate to support both the patient's head and a Leksell stereotactic skull frame during frame placement in the supine position. The base plate is made of transparent acrylic board with holes at the posterior posts for injection of local anesthetics and maneuver of fixation screws through them. A stable and comfortable position of the patient's head in a supine position is obtained and maintained on this base plate with an air-pressure cuff beneath the patient's head. The patient is able to keep a stable, relaxed and comfortable posture during the procedures of skull frame placement.

Gamma knife radiosurgery of brain metastasis from malignant pleural mesothelioma--report of three cases with autopsy study in a case.

The median survival time of malignant pleural mesothelioma (MPM) has been 9 months. Given the short survival, there have been only few cases in which brain metastases have been diagnosed and treated before death. Three cases of brain metastases treated by gamma knife radiosurgery (GKR) are reported. Case I showed a metastatic lesion in the right frontal lobe which was treated by GKR two years after diagnosis of MPM. The lesion markedly reduced and the symptoms were improved, But the patient died of progression of pleural tumor four months after GKR. A year and three months after the diagnosis, asymptomatic bifrontal lesions were treated with GKR. However, Case 2 died of abdominal mass a month after. Case 3 showed headache one and half year after the diagnosis. Three brain lesions were treated by GKR, which disappeared in 4 months. The patient died of new multiple brain metastases and periventricular dissemination seven months after. The autopsy revealed a MPM occupying the left pleural cavity. No neoplastic lesion was found in gamma knife-treated sites. The cause of death was the mass effect by new metastatic lesions. GKR was found effective also for the treatment of brain metastasis of MPM.

Effect of skull contours on dose calculations in Gamma Knife Perfexion stereotactic radiosurgery.

In treatment planning of Leksell Gamma Knife (LGK) radiosurgery, the skull geometry defined by generally dedicated scalar measurement has a crucial effect on dose calculation. The LGK Perfexion (PFX) unit is equipped with a cone-shaped collimator divided into eight sectors, and its configuration is entirely different from previous model C. Beam delivery on the PFX is made by a combination of eight sectors, but it is also mechanically available from one sector with the remaining seven blocked. Hence the treatment time using one sector is more likely to be affected by discrepancies in the skull shape than that of all sectors. In addition, the latest version (Ver. 10.1.1) of the treatment planning system Leksell GammaPlan (LGP) includes a new function to directly generate head surface contouring from computed tomography (CT) images in conjunction with the Leksell skull frame. This paper evaluates change of treatment time induced by different skull models. A simple simulation using a uniform skull radius of 80 mm and anthropomorphic phantom was implemented in LGP to find the trend between dose and skull measuring error. To evaluate the clinical effect, we performed an interobserver comparison of ruler measurement for 41 patients, and compared instrumental and CT-based contours for 23 patients. In the phantom simulation, treatment time errors were less than 2% when the difference was within 3 mm. In the clinical cases, the variability of treatment time induced by the differences in interobserver measurements was less than 0.91%, on average. Additionally the difference between measured and CT-based contours was good, with a difference of -0.16% ± 0.66% (mean ±1 standard deviation) on average and a maximum of 3.4%. Although the skull model created from CT images reduced the dosimetric uncertainty caused by different measurers, these results showed that even manual skull measurement could reproduce the skull shape close to that of a patient's head within an acceptable range.

Outcomes and Prognostic Factors of Magnetic Resonance-guided Focused Ultrasound Thalamotomy for Essential Tremor at 2-year Follow-up.

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for essential tremor (ET). However, its long-term outcomes and prognostic factors remain unclear. This study aimed to retrospectively investigate 38 patients with ET who underwent MRgFUS thalamotomy and were followed up for >2 years. The improvement in tremor was evaluated using the Clinical Rating Scale for Tremor (CRST). Adverse events were documented, and correlations with factors, such as skull density ratio (SDR), maximum mean temperature (T-max), and lesion size, were examined. Furthermore, the outcomes were compared between two groups, one that met the cutoff values, which was previously reported (preoperative CRST-B ≤ 25, T-max ≥ 52.5°C, anterior-posterior size of lesion ≥ 3.9 mm, superior-inferior [SI] size of lesion > 5.5 mm), and the other that did not. The improvement rate was 59.4% on average at the 2-year follow-up. Adverse events, such as numbness (15.8%), dysarthria (10.5%), and lower extremity weakness (2.6%), were observed even after 2 years, although these were mild. The factors correlated with tremor improvement were the T-max and SI size of the lesion (p < 0.05), whereas the SDR showed no significance. Patients who met the aforementioned cutoff values demonstrated a 69.8% improvement at the 2-year follow-up, whereas others showed a 43.6% improvement (p < 0.05). In conclusion, MRgFUS is effective even after 2 years. The higher the T-max and the larger the lesion size, the better the tremor control. Previously reported cutoff values clearly predict the 2-year prognosis, indicating the usefulness of MRgFUS.

Gamma knife stereotactic radiosurgery for atypical and malignant meningiomas.

BACKGROUND: Non-benign meningioma has a known trend to recur repeatedly. The results of Gamma Knife stereotactic radiosurgery (GKS) for recurrent or residual atypical and malignant meningiomas are reported. METHODS: Thirty patients (13 men, 17 women) with World Health Organization (WHO) grade II (24 cases) or grade III (6 cases) intracranial meningiomas underwent GKS. Their age varied from 30 to 86 years (mean 64 years). Before GKS, the tumor was surgically resected in all patients, and 11 of them also underwent conventional external beam radiation therapy, LINAC-based stereotactic radiotherapy (SRT), or intensity-modulated radiation therapy. FINDINGS: Of the 30 patients, 23 were followed after the initial GKS for a median period of 28 months (range 2-135 months). Local tumor control after treatment was 74 % at 1 year, 52 % at 2 years, and 34 % at 3 years. A total of 15 patients underwent repeat GKS (one to nine times) because of local or distant intracranial tumor progression, seven were subjected to surgical re-resection of the neoplasm, and four had additional SRT. At the time of the last follow-up, 21 patients were alive, and 2 had died. One of the latter expired because of brain tumor progression at 91 months after the initial GKS, and the other patient died from lung cancer. CONCLUSIONS: Although atypical and malignant meningiomas have a trend to recur repeatedly, aggressive tumor management with repeat GKS at the time of progression can provide long survival in these patients.

Stereotactic radiotherapy for spinal intradural metastases developing within or adjacent to the previous irradiation field--report of three cases.

Results of stereotactic radiotherapy (SRT) for spinal intradural metastases developing inside or adjacent to the previous external-beam radiation therapy (EBRT) field are shown in 3 cases. One case of spinal intramedullary metastasis and two cases of intradural extramedullary metastases were treated using a Novalis shaped-beam SRT. Case 1 developed an intramedullary metastatic tumor in the C1 spinal medulla inside the previous whole brain EBRT field and another lesion adjacent to the field in the C2 spinal medulla. Case 2 developed intradural extramedullary metastasis around C6-8 inside the previous EBRT field for the primary lung adenocarcinoma. Case 3 developed multiple spinal intradural extramedullary metastatic deposits after surgical resection and following whole brain EBRT for brain metastasis. We delivered 24 to 36 Gy in 5 to 12 fractions. The treated tumors were stable or decreased in size until the patients' death from the primary cancer (10, 22, and 5 months). Neurological symptoms were stable or improved in all 3 patients. Palliative SRT using Novalis is expected to be safe and effective even if the patient develops spinal intradural metastases within or adjacent to the previous irradiation field.

Magnetic resonance-guided focused ultrasound thalamotomy restored distinctive resting-state networks in patients with essential tremor.

OBJECTIVE: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy ameliorates symptoms in patients with essential tremor (ET). How this treatment affects canonical brain networks has not been elucidated. The purpose of this study was to clarify changes of brain networks after MRgFUS thalamotomy in ET patients by analyzing resting-state networks (RSNs). METHODS: Fifteen patients with ET were included in this study. Left MRgFUS thalamotomy was performed in all cases, and MR images, including resting-state functional MRI (rsfMRI), were taken before and after surgery. MR images of 15 age- and sex-matched healthy controls (HCs) were also used for analysis. Using rsfMRI data, canonical RSNs were extracted by performing dual regression analysis, and the functional connectivity (FC) within respective networks was compared among pre-MRgFUS patients, post-MRgFUS patients, and HCs. The severity of tremor was evaluated using the Clinical Rating Scale for Tremor (CRST) score pre- and postoperatively, and its correlation with RSNs was examined. RESULTS: Preoperatively, ET patients showed a significant decrease in FC in the sensorimotor network (SMN), primary visual network (VN), and visuospatial network (VSN) compared with HCs. The decrease in FC in the SMN correlated with the severity of tremor. After MRgFUS thalamotomy, ET patients still exhibited a significant decrease in FC in a small area of the SMN, but they exhibited an increase in the cerebellar network (CN). In comparison between pre- and post-MRgFUS patients, the FC in the SMN and the VSN significantly increased after treatment. Quantitative evaluation of the FCs in these three groups showed that the SMN and VSN increased postoperatively and demonstrated a trend toward those of HCs. CONCLUSIONS: The SMN and CN, which are considered to be associated with the cerebello-thalamo-cortical loop, exhibited increased connectivity after MRgFUS thalamotomy. In addition, the FC of the visual network, which declined in ET patients compared with HCs, tended to normalize postoperatively. This could be related to the hypothesis that visual feedback is involved in tremor severity in ET patients. Overall, the analysis of the RSNs by rsfMRI reflected the pathophysiology with the intervention of MRgFUS thalamotomy in ET patients and demonstrated a possibility of a biomarker for successful treatment.

Prognostic factors for tumor recurrence after gamma knife radiosurgery of partially resected and recurrent craniopharyngiomas.

A study was conducted to clarify the prognostic factors related to recurrence of craniopharyngioma and to improve the quality of life of patients by the treatment with intentional partial removal and gamma knife radiosurgery. One hundred cases of craniopharyngioma have been treated at Komaki City Hospital since 1991. In a mean follow-up period of 65.5 months, the tumor control rate was 79.5%. The 5- and 10-year actuarial survival rates were 94.1% and 91%, respectively. However, the recurrence-free survival rates were 73.6% at 5 years and 60.2% at 10 years. Nine factors thought to be related to the recurrence were selected from past references and previous studies, including gender, age, pediatric (< or =17 years) or adult patient, partial removal or recurrence, mean tumor diameter, tumor type (solid or cyst), pathological types (squamous cell or adamantinoma), number of previous treatments, and radiation dose. Statistical analysis was performed to determine which factors had a significant prognostic impact. Multivariate analysis showed that mean tumor diameter and radiation dose were independent predictors of outcome. To maximize the prognostic power of these factors, cut-off levels were determined using ROC analysis. These levels were 19 mm for tumor diameter and 13.2 Gy for marginal dose. Significant prognostic factors related to recurrence of craniopharyngioma are tumor diameter and radiation dose. A tumor diameter of <19 mm and a marginal dose of > or =13.2 Gy are favorable prognostic factors for gamma knife radiosurgery.

Cutoff values for the best management strategy for magnetic resonance-guided focused ultrasound ablation for essential tremor.

OBJECTIVE: The efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) ablation for essential tremor (ET) is well known; however, no prognostic factors have been established. The authors aimed to retrospectively investigate MRgFUS ablation outcomes and associated factors and to define the cutoff values for each prognostic factor. METHODS: Sixty-four Japanese patients who underwent unilateral ventral intermediate nucleus thalamotomy with MRgFUS for ET were included. Follow-up evaluations were performed at 1 week and 1, 3, 6, 12, and 24 months postoperatively. Tremor suppression was evaluated using the Clinical Rating Scale for Tremor (CRST), and adverse effects were recorded postoperatively. Outcome-associated factors were examined preoperatively, intraoperatively, and postoperatively using multivariate analyses. The cutoff values for the prognostic factors were calculated using receiver operating characteristics. RESULTS: Percentage improvements in the CRST scores of the affected upper limb were 82.4%, 72.2%, 68.6%, and 65.9% at 1, 3, 6, and 12 months, respectively. Preoperatively, a high skull density ratio (SDR) (p ≤ 0.047), low CRST part B score (used to assess tremors during several tasks) (cutoff value 25, p ≤ 0.041), and nonoccurrence of resting tremors (p = 0.027) were significantly associated with improved tremor control. An intraoperatively high maximum mean temperature (cutoff value 52.5°C, p ≤ 0.047), postoperatively large lesion (cutoff value 3.9 mm in the anterior-posterior direction, p ≤ 0.002; cutoff value 5.0-5.55 mm in the superior-inferior direction, p ≤ 0.026), and small transducer focus correction (p ≤ 0.015) were also associated with improved tremor control. No valid cutoff value was found for SDR. Adverse effects (limb weakness, sensory disturbance, ataxia/walking disturbance, dysgeusia, dysarthria, and facial swelling) occurred transiently and were associated with high SDR, high temperature, high number of sonication sessions, large lesion, and occurrence of resting tremor. Patients who developed leg weakness experienced greater percentage improvement in tremors at 3 months postoperatively than those who did not. CONCLUSIONS: MRgFUS ablation could be used to achieve good tremor control with acceptable adverse effects in Japanese patients with ET. The relatively low SDR in Asian ethnic groups as compared with that of Western populations makes treatment difficult; however, the cutoff values obtained in this study may be useful for achieving good treatment outcomes even in such patients. Clinical trial registration no.: UMIN000026952 (University Hospital Medical Information Network). ABBREVIATIONS: ACPC = anterior commissure-posterior commissure; AP = anterior to posterior; CRST = Clinical Rating Scale for Tremor; ET = essential tremor; MRgFUS = magnetic resonance-guided focused ultrasound; PC = posterior commissure; PSA = posterior subthalamic area; RL = right to left; ROC = receiver operating characteristic; SDR = skull density ratio; SI = superior to inferior; T2WI = T2-weighted imaging; VIM = ventral intermediate nucleus.

11C-methionine- and 18F-FDG-PET double-negative metastatic brain tumor from lung adenocarcinoma with paradoxical high 18F-FDG uptake: A case report.

Background: Imaging with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and 11C-methionine (MET)-PET can delineate primary and metastatic brain tumors. Lesion size affects the sensitivity of both scans and histopathological features can also influence FDG-PET, but the effects on MET-PET have not been elucidated. Case Description: We report an unusual case of metastatic brain tumors without accumulation of FDG or MET, contrasting with high FDG uptake in the primary lung lesion. The brain lesions were identified as adenocarcinoma with a more mucus-rich background, contributing to the indistinct accumulation of both FDG and MET. Conclusion: Histopathological characteristics can affect both MET and FDG accumulation, leading to findings contradicting those of the primary lesion.

Techniques, Indications, and Outcomes in Magnetic Resonance-guided Focused Ultrasound Thalamotomy for Tremor.

Magnetic resonance (MR)-guided focused ultrasound surgery (MRgFUS) is the latest minimally invasive stereotactic procedure, and thalamotomy using this novel modality has demonstrated its effectiveness and safety, especially for patients with essential tremor (ET) and Parkinson's disease (PD). In Japan, the application of MRgFUS to treat ET and PD has recently been covered by health insurance. Technically, the transducer with 1024 elements emits ultrasound beams, which are then focused on the target with a phase control, resulting in optimal ablation by thermal coagulation. The technical advantages of MRgFUS are continuous intraoperative monitoring of clinical symptoms and MR images and fine adjustment of the target by the steering function. Postoperative tremor control is compatible with other modalities, although long-term follow-up is necessary. The adverse effects are usually transient and acceptable. Prognostic factors for good tremor control include high temperature and large lesion size. A high skull density ratio is a factor to achieve high temperature and large lesioning, but it may not be necessary and sufficient for clinical outcomes. For patients with advanced symptoms such as bilateral tremor or head/neck tremor, deep brain stimulation may be recommended because of the adjustability of stimulation and the possibility of bilateral treatment. Patients have high expectations of MRgFUS because of its non-invasiveness. To perform this treatment safely and effectively, physicians need to understand the technological aspects, the physiological principles. To choose the appropriate modality, physicians also should recognize the clinical advantages and disadvantages of MRgFUS compared to other modalities.

Gamma Knife Surgery for Residual or Recurrent Craniopharyngioma After Surgical Resection: A Multi-institutional Retrospective Study in Japan.

Objective The optimal treatment for a craniopharyngioma has been controversial. Complete resection is ideal, but it has been difficult to obtain total resection in many cases because of intimate proximity to critical structures such as the optic pathway, hypothalamus, and pituitary gland. A growing number of studies have demonstrated the utility of radiosurgery in controlling residual or recurrent craniopharyngioma. However, most of them are small series. The aim of this multi-institutional study was to clarify the efficacy and safety of Gamma Knife (Elekta, Stockholm, Sweden) surgery for patients with a craniopharyngioma. Methods This was a multi-institutional retrospective study by 16 medical centers of the Japan Leksell Gamma Knife Society. Data on patients with craniopharyngiomas treated with Gamma Knife Surgery (GKS) between 1991 and 2013 were obtained from individual institutional review board-approved databases at each center. A total of 242 patients with craniopharyngioma were included in this study. The mean age of the patients was 41 (range, 3 to 86) years. The median follow-up time was 61.4 months (range, 3 to 180 months). The mean radiosurgery target volume was 3.1 ml (range, 0.03-22.3 ml), and the mean marginal dose was 11.4 Gy (range, 8-20.4 Gy). Results Two-hundred twenty patients were alive at the time of the last follow-up visit. The three-, five-, and 10-year overall survival rates after GKS were 95.4%, 92.5%, and 82.0%, respectively. The three-, five-, and 10-year progression-free survival rates after GKS were 73.1%, 62.2%, and 42.6% respectively. The rate of radiation-induced complications was 6.2%. Conclusion GKS is effective for controlling the tumor growth of craniopharyngiomas with an acceptable complication rate.

Stereotactic Radiotherapy for Intramedullary Spinal Arteriovenous Malformations.

Introduction Preliminary results of stereotactic radiotherapy (SRT) for spinal arteriovenous malformation (AVM) in five cases are presented.  Methods Two cases were male and three were female. Their median age was 32 years (range: 23 to 54 years). The spinal intramedullary AVMs were located in the cervical spine in three and in the thoracic spine in two. SRT with 20 Gy in four fractions was delivered to the nidus in every case. Results At the end of the median follow-up period of 5.5 years (range: 3 to 8.5 years), the neurological symptoms and signs were improved or unchanged as compared with before treatment, although a temporary adverse effect developed between a half year and one year after SRT in one case. The nidi were obliterated five and a half years after SRT in one case and three years after SRT in one. In the other three cases, the nidi were unchanged. Conclusion SRT with 20 Gy in four fractions was thought to be a safe treatment, though this study dealt with only a small number of patients with a short-term follow-up period.

Delivery of interferon-alpha transfected dendritic cells into central nervous system tumors enhances the antitumor efficacy of peripheral peptide-based vaccines.

We evaluated the effects, on immunity and survival, of injection of interferon (IFN)-alpha-transfected dendritic cells (DC-IFN-alpha) into intracranial tumors in mice immunized previously with syngeneic dendritic cells (DCs) pulsed either with ovalbumin-derived CTL or T helper epitopes. These immunizations protected animals from s.c. challenge with ovalbumin-expressing M05 melanoma (class I+ and class II-negative). Notably, antiovalbumin CTL responses were observed in animals vaccinated with an ovalbumin-derived T helper epitope but only after the mice were challenged with M05 cells. This cross-priming of CTL was dependent on both CD4+ and CD8+ T cells. Because we observed that s.c., but not intracranial, tumors were infiltrated with CD11c+ DCs, and because IFN-alpha promotes the activation and survival of both DCs and T cells, we evaluated the combinational antitumor effects of injecting adenoviral (Ad)-IFN-alpha-engineered DCs into intracranial M05 tumors in preimmunized mice. Delivery of DC-IFN-alpha prolonged survival. This was most notable for animals prevaccinated with both the CTL and T helper ovalbumin epitopes, with 60% (6 of 10) of mice (versus 0 of 10 of control animals) surviving for > 80 days after tumor challenge. DC-IFN-alpha appeared to persist longer than mock-transfected DCs within the intracranial tumor microenvironment, and DC-IFN-alpha-treated mice exhibited enhanced levels of ovalbumin-specific CTL in draining cervical lymph nodes. On the basis of these results, we believe that local expression of IFN-alpha by DCs within the intracranial tumor site may enhance the clinical efficacy of peripheral vaccine approaches for brain tumors.

Gamma Knife surgery for patients with facial nerve schwannomas: a multiinstitutional retrospective study in Japan.

OBJECTIVE: The aim of this study was to explore the efficacy and safety of stereotactic radiosurgery for patients with facial nerve schwannomas (FNSs). METHODS: This study was a multiinstitutional retrospective analysis of 42 patients with FNSs treated with Gamma Knife surgery (GKS) at 1 of 10 medical centers of the Japan Leksell Gamma Knife Society (JLGK1301). The median age of the patients was 50 years. Twenty-nine patients underwent GKS as the initial treatment, and 13 patients had previously undergone surgery. At the time of the GKS, 33 (79%) patients had some degree of facial palsy, and 21 (50%) did not retain serviceable hearing. Thirty-five (83%) tumors were solid, and 7 (17%) had cystic components. The median tumor volume was 2.5 cm(3), and the median prescription dose to the tumor margin was 12 Gy. RESULTS: The median follow-up period was 48 months. The last follow-up images showed partial remission in 23 patients and stable tumors in 19 patients. Only 1 patient experienced tumor progression at 60 months, but repeat GKS led to tumor shrinkage. The actuarial 3- and 5-year progression-free survival rates were 100% and 92%, respectively. During the follow-up period, 8 patients presented with newly developed or worsened preexisting facial palsy. The condition was transient in 3 of these patients. At the last clinical follow-up, facial nerve function improved in 8 (19%) patients, remained stable in 29 (69%), and worsened in 5 (12%; House-Brackmann Grade III in 4 patients, Grade IV in 1 patient). With respect to hearing function, 18 (90%) of 20 evaluated patients with a pure tone average of ≤ 50 dB before treatment retained serviceable hearing. CONCLUSIONS: GKS is a safe and effective treatment option for patients with either primary or residual FNSs. All patients, including 1 patient who required repeat GKS, achieved good tumor control at the last follow-up. The incidence of newly developed or worsened preexisting facial palsy was 12% at the last clinical follow-up. In addition, the risk of hearing deterioration as an adverse effect of radiation was low. These results suggest that GKS is a safe alternative to resection.